Claudette E. Loo

Magnetic Resonance Imaging Response Monitoring of Breast Cancer During Neoadjuvant Chemotherapy: Relevance of Breast Cancer Subtype

PURPOSE To evaluate the relevance of breast cancer subtypes for magnetic resonance imaging (MRI) markers for monitoring of therapy response during neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS MRI examinations were performed in 188 women before and during NAC. MRI interpretation included lesion morphology at baseline, changes in morphology, size, and contrast uptake kinetics (initial and late enhancement). By using immunohistochemistry, tumors were divided into three subtypes: triple negative, human epidermal growth factor receptor 2 (HER2) positive, and estrogen receptor (ER) positive/HER2 negative. Tumor response was assessed dichotomously (ie, presence or absence of residual tumor in the surgical specimen). Complementary, a continuous scale assessment was used (the breast response index [BRI], representing the relative change in tumor stage). Multivariate regression analysis and receiver operating characteristic analysis were employed to establish significant associations. RESULTS Residual tumor at pathology was present in 31 (66%) of 47 triple-negative tumors, 23 (61%) of 38 HER2-positive tumors, and 96 (93%) of 103 ER-positive/HER2-negative tumors. Multivariate analysis of residual disease showed significant associations between breast cancer subtype and MRI (area under the curve [AUC], 0.84; P < .001). BRI also showed significant correlation among breast cancer subtype, MRI, and age (Pearsons r = 0.465; P < .001). In subset analysis, this was only significant for triple-negative tumors (P < .001) and HER2-positive tumors (P < .05). Residual tumor after NAC in the triple-negative and HER2-positive group is significantly associated with the change in largest diameter of late enhancement during NAC (AUC, 0.76; P < .001). No associations were found for ER-positive/HER2-negative tumors. CONCLUSION MRI during NAC to monitor response is effective in triple-negative or HER2-positive disease but is inaccurate in ER-positive/HER2-negative breast cancer.

Changes in Gene Expression Associated With Response to Neoadjuvant Chemotherapy in Breast Cancer

PURPOSE At present, clinically useful markers predicting response of primary breast carcinomas to either doxorubicin-cyclophosphamide (AC) or doxorubicin-docetaxel (AD) are lacking. We investigated whether gene expression profiles of the primary tumor could be used to predict treatment response to either of those chemotherapy regimens. PATIENTS AND METHODS Within a single-institution, randomized, phase II trial, patients with locally advanced breast cancer received six courses of either AC (n = 24) or AD (n = 24) neoadjuvant chemotherapy. Gene expression profiles were generated from core-needle biopsies obtained before treatment and correlated with the response of the primary tumor to the chemotherapy administered. Additionally, pretreatment gene expression profiles were compared with those in tumors remaining after chemotherapy. RESULTS Ten (20%) of 48 patients showed a (near) pathologic complete remission of the primary tumor after treatment. No gene expression pattern correlating with response could be identified for all patients or for the AC or AD groups separately. The comparison of the pretreatment biopsy and the tumor excised after chemotherapy revealed differences in gene expression in tumors that showed a partial remission but not in tumors that did not respond to chemotherapy. CONCLUSION No gene expression profile predicting the response of primary breast carcinomas to AC- or AD-based neoadjuvant chemotherapy could be detected in this interim analysis. More subtle differences in gene expression are likely to be present but can only be reliably identified by studying a larger group of patients. Response of a breast tumor to neoadjuvant chemotherapy results in alterations in gene expression.

Breast tomosynthesis in clinical practice: initial results

The purpose of this study was to assess the potential value of tomosynthesis in women with an abnormal screening mammogram or with clinical symptoms. Mammography and tomosynthesis investigations of 513 woman with an abnormal screening mammogram or with clinical symptoms were prospectively classified according to the ACR BI-RADS criteria. Sensitivity and specificity of both techniques for the detection of cancer were calculated. In 112 newly detected cancers, tomosynthesis and mammography were each false-negative in 8 cases (7%). In the false-negative mammography cases, the tumor was detected with ultrasound (n = 4), MRI (n = 2), by recall after breast tomosynthesis interpretation (n = 1), and after prophylactic mastectomy (n = 1). Combining the results of mammography and tomosynthesis detected 109 cancers. Therefore in three patients, both mammography and tomosynthesis missed the carcinoma. The sensitivity of both techniques for the detection of breast cancer was 92.9%, and the specificity of mammography and tomosynthesis was 86.1 and 84.4%, respectively. Tomosynthesis can be used as an additional technique to mammography in patients referred with an abnormal screening mammogram or with clinical symptoms. Additional lesions detected by tomosynthesis, however, are also likely to be detected by other techniques used in the clinical work-up of these patients.

BRCA1-Associated Breast Cancers Present Differently From BRCA2-Associated and Familial Cases: Long-Term Follow-Up of the Dutch MRISC Screening Study

PURPOSE The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Dynamic Contrast-Enhanced MRI for Prediction of Breast Cancer Response to Neoadjuvant Chemotherapy: Initial Results

OBJECTIVE The aim of this study was to establish changes in contrast-enhanced MRI of breast cancer during neoadjuvant chemotherapy that are indicative of pathology outcome. MATERIALS AND METHODS In 54 patients with breast cancer, dynamic contrast-enhanced MRI was performed before chemotherapy and after two chemotherapy cycles. Imaging was correlated with final histopathology. Multivariate analysis with cross-validation was performed on MRI features describing kinetics and morphology of contrast uptake in the early and late phases of enhancement. Receiver operating characteristic (ROC) analysis was used to develop a guideline that switches patients at high risk for incomplete remission to a different chemotherapy regimen while maintaining first-line therapy in 95% of patients who are not at risk (i.e., high specificity). RESULTS Change in largest diameter of late enhancement during chemotherapy was the single most predictive MRI characteristic for tumor response in multivariate analysis (A(z) [area under the ROC curve] = 0.73, p < 0.00001). Insufficient (< 25%) decrease in largest diameter of late enhancement during chemotherapy was most indicative of residual tumor at final pathology. Using this criterion, the fraction of unfavorable responders indicated by MRI was 41% (22/54). Approximately half (44%, 14/32) of the patients who showed favorable response at MRI achieved complete remission at pathology. Conversely, 95% (21/22) of patients who showed unfavorable response at MRI had residual tumor at pathology. CONCLUSION Reduction of less than 25% in largest diameter of late enhancement during neoadjuvant chemotherapy shows the potential to predict residual tumor after therapy with high specificity.

Risk of invasion and axillary lymph node metastasis in ductal carcinoma in situ diagnosed by core-needle biopsy

The aim of the study was to assess the risk of invasion and axillary lymph node metastasis in patients with ductal carcinoma in situ (DCIS) diagnosed by preoperative core‐needle biopsy. The data were used to select criteria for patients in whom sentinel node (SN) biopsy might be indicated.

Radioactive Seed Localization of Breast Lesions: An Adequate Localization Method without Seed Migration

Abstract:  Preoperative localization is important to optimize the surgical treatment of breast lesions, especially in nonpalpable lesions. Radioactive seed localization (RSL) using iodine‐125 is a relatively new approach. To provide accurate guidance to surgery, it is important that the seeds do not migrate after placement. The aim of this study was to assess short‐term and long‐term seed migration after RSL of breast lesions. In 45 patients, 48 RSL procedures were performed under ultrasound or stereotactic guidance. In the first 12 patients, the lesion was localized with two markers: an iodine‐125 seed and a reference marker. In 33 patients, 36 RSL procedures were performed using a single iodine‐125 seed. All patients received control mammograms after seed placement and prior to surgery. In the patients with two markers, migration was defined as the difference in the largest distance between the markers observed in the mammograms. For single‐marked lesions, migration was assessed by comparing distances between anatomical landmarks in the mammograms. RSL was successful in all patients. Seeds were in‐situ for 59.5 days on average (3–136 days). The detection rate during surgery was 100%. Overall, an average seed migration of 0.9 mm (standard deviation 1.0 mm) was observed. Neither differences in lesion type, nor days in situ, type of surgery or radiologic localization method were found to have impact on seed migration. RSL is an accurate preoperative localization method for breast lesions with negligible seed migration, independent of time in‐situ.

Marking the axilla with radioactive iodine seeds (MARI procedure) may reduce the need for axillary dissection after neoadjuvant chemotherapy for breast cancer

An important benefit of neoadjuvant chemotherapy is the increased potential for breast‐conserving surgery. At present the response of axillary lymph node metastases to chemotherapy is not easily assessed, rendering axilla‐conserving treatment difficult. The aim was to assess a new surgical method for evaluating the axillary response to chemotherapy.

Precise correlation between MRI and histopathology - Exploring treatment margins for MRI-guided localized breast cancer therapy

BACKGROUND Magnetic resonance imaging (MRI) is more often considered to guide, evaluate or select patients for partial breast irradiation (PBI) or minimally invasive therapy. Safe treatment margins around the MRI-visible lesion (MRI-GTV) are needed to account for surrounding subclinical occult disease. PURPOSE To precisely compare MRI findings with histopathology, and to obtain detailed knowledge about type, rate, quantity and distance of occult disease around the MRI-GTV. METHODS AND MATERIALS Patients undergoing MRI and breast-conserving therapy were prospectively included. The wide local excision specimens were subjected to detailed microscopic examination. The size of the invasive (index) tumor was compared with the MRI-GTV. The gross tumor volume (GTV) was defined as the pre-treatment visible lesion. Subclinical tumor foci were reconstructed at various distances to the MRI-GTV. RESULTS Sixty-two patients (64 breasts) were included. The mean size difference between MRI-GTV and the index tumor was 1.3mm. Subclinical disease occurred in 52% and 25% of the specimens at distances ≥10mm and ≥20mm, respectively, from the MRI-GTV. CONCLUSIONS For MRI-guided minimally invasive therapy, typical treatment margins of 10mm around the MRI-GTV may include occult disease in 52% of patients. When surgery achieves a 10mm tumor-free margin around the MRI-GTV, radiotherapy to the tumor bed may require clinical target volume margins >10mm in up to one-fourth of the patients.

Sentinel Node Biopsy and Concomitant Probe-Guided Tumor Excision of Nonpalpable Breast Cancer

BackgroundPreliminary data have shown encouraging results of a single intratumoral radiopharmaceutical injection that enables both sentinel node biopsy and probe-guided excision of the primary tumor in patients with nonpalpable breast cancer. The aim of the study was to evaluate this approach in a large group of patients.MethodsLymphoscintigraphy was performed in 368 patients with nonpalpable breast cancer after intratumoral injection of 99mTc-nanocolloid (.2 mL, 123 MBq, 3.3 mCi) guided by ultrasound or stereotaxis. The sentinel node was pursued with the aid of vital blue dye (1.0 mL, intratumoral) and a gamma ray detection probe. In case of breast-conserving surgery, the probe was used to guide the excision.ResultsAt least one sentinel node could be identified intraoperatively in 357 patients (97%), of whom 69 had involved nodes (19%). Age over 60 years was associated with less frequent nonaxillary lymphatic drainage and absence of internal mammary chain dissemination. Tumor-free margins were obtained in 262 (89%) of the 293 patients who underwent segmental excision. Re-excision of the primary tumor bed was performed in six patients (2%). During a median follow-up of 22 months, one breast recurrence and one axillary recurrence were observed.ConclusionsLymphatic mapping and probe-guided tumor excision of nonpalpable breast cancer by intralesional administration of a single dose of 99mTc-nanocolloid and blue dye resulted in 97% identification of the sentinel node and in tumor-free margins in 89% of the patients who underwent breast-conserving surgery. Longer follow-up is needed to substantiate the accuracy and safety of this technique.